Patients on Statins With Elevated Transaminases: Frequency of Follow-up Creatine Kinase Testing and Gastroenterology Referral

Patients on Statins With Elevated Transaminases: Frequency of Follow-up Creatine Kinase Testing and Gastroenterology Referral | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL British Journal of Clinical Pharmacology This is a preprint and has not been peer reviewed. Data may be preliminary. 18 December 2025 V1 Latest version Share on Patients on Statins With Elevated Transaminases: Frequency of Follow-up Creatine Kinase Testing and Gastroenterology Referral Authors : Faris Shweikeh [email protected] , Anas Kartoumah 0009-0006-7269-498X , Rajshri Joshi , Anjali Nadihaan , Mohammed Mouchli , and Inderprit Singh Authors Info & Affiliations https://doi.org/10.22541/au.176607106.62218538/v1 Published British Journal of Clinical Pharmacology Version of record Peer review timeline 458 views 97 downloads Contents Abstract Transparency & Reproducibility Statement (recommended by PDS) Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Purpose: To quantify how often creatine kinase (CK) is measured after newly elevated aminotransferases in statin users, and whether absent CK data is associated with gastroenterology (GI) referrals. Methods: Retrospective chart review of adult outpatients on statins with a first alanine/aspartate aminotransferase (ALT/AST) elevation during a 5-year period at a large health system. The primary outcome was CK testing within 30 days; secondary outcomes included CK elevation rate and GI referral within 60 days. Results: Among 806 eligible patients, 22.8% (184/806) had CK measured within 30 days (median 9 days; IQR 5–17). Of those tested, 15.8% (29/184) had CK above the upper limit of normal (ULN); 3.6% (29/806) of the entire cohort therefore had unrecognized biochemical evidence of muscle injury. None had documented rhabdomyolysis, acute kidney injury, or hospitalization. Among patients without timely CK testing (619/806), 4.7% (29/619) were referred to GI within 60 days; this proportion (3.6% of the total cohort) mirrored the fraction with CK elevation, suggesting potentially avoidable hepatic work-ups in the absence of muscle-specific testing. Conclusions: In routine practice, CK is infrequently measured after new ALT/AST elevations in statin users, yet a non-trivial subset has biochemical myopathy. Reflex CK testing at the first abnormal transaminase could improve diagnostic accuracy and reduce unnecessary GI referrals while preserving effective lipid-lowering therapy. Prospective evaluation of reflex-testing pathways and tailored statin selection/dosing is warranted. Title: Patients on Statins With Elevated Transaminases: Frequency of Follow-up Creatine Kinase Testing and Gastroenterology Referral Running title: CK testing after statin-related LFT rise Authors: Faris Shweikeh 1 , Anas Kartoumah, Rajshri Joshi 1 , Anjali Nadihaan 1 , Mohammed Mouchli 2,3 , Inderprit Singh 4 Affiliations: 1) Department of Internal Medicine, Cleveland Clinic Akron General, Akron, OH, 2) University of South Florida, Tampa, FL 3) Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 4)Division of Gastroenterology and Hepatology, Department of Internal Medicine, Fisher Titus Medical Center, Norwalk, Ohio 5) Department of Rheumatology and Immunology, Cleveland Clinic Akron General, Akron, OH Corresponding author: Faris Shweikeh, [email protected] , 951-522-3615 Funding: None. Conflicts of interest: The authors declare no conflicts of interest. Ethics/IRB approval: This study was reviewed and approved by the Institutional Review Board of Cleveland Clinic, which granted a waiver of informed consent for this minimal risk retrospective chart review. Prior presentation: None. Word counts: Abstract: 234; Main text: 3516; Tables: 2; Figures: 1; References: 24 Keywords: statins; creatine kinase; liver function tests; pharmacovigilance; myopathy; rhabdomyolysis; pharmacoepidemiology Author Contributions Conceptualization: FS, RJ, AN; Methodology: FS, RJ, AN; Data curation: AK, RJ, AN; Formal analysis: FS, MM, IS; Investigation: AK, RJ, AN; Writing—FS, AK, RJ, AN: Writing—review & editing: [all authors]; Supervision: FS, MM, IS. Acknowledgments None. Purpose: To quantify how often creatine kinase (CK) is measured after newly elevated aminotransferases in statin users, and whether absent CK data is associated with gastroenterology (GI) referrals. Methods: Retrospective chart review of adult outpatients on statins with a first alanine/aspartate aminotransferase (ALT/AST) elevation during a 5-year period at a large health system. The primary outcome was CK testing within 30 days; secondary outcomes included CK elevation rate and GI referral within 60 days. Results: Among 806 eligible patients, 22.8% (184/806) had CK measured within 30 days (median 9 days; IQR 5–17). Of those tested, 15.8% (29/184) had CK above the upper limit of normal (ULN); 3.6% (29/806) of the entire cohort therefore had unrecognized biochemical evidence of muscle injury. None had documented rhabdomyolysis, acute kidney injury, or hospitalization. Among patients without timely CK testing (619/806), 4.7% (29/619) were referred to GI within 60 days; this proportion (3.6% of the total cohort) mirrored the fraction with CK elevation, suggesting potentially avoidable hepatic work-ups in the absence of muscle-specific testing. Conclusions: In routine practice, CK is infrequently measured after new ALT/AST elevations in statin users, yet a non-trivial subset has biochemical myopathy. Reflex CK testing at the first abnormal transaminase could improve diagnostic accuracy and reduce unnecessary GI referrals while preserving effective lipid-lowering therapy. Prospective evaluation of reflex-testing pathways and tailored statin selection/dosing is warranted. Statins lower cholesterol and prevent heart attacks and strokes, but they can rarely affect muscles or the liver. Doctors often see small rises in liver enzymes (ALT/AST) on blood tests and may assume the liver is the cause. We reviewed 806 outpatients on statins who developed new ALT/AST elevations. Only about one in four had a muscle test (creatine kinase, CK) within 30 days. Among those who were tested, about one in six had an elevated CK, meaning muscle injury was likely. Overall, 3.6% of the entire group had elevated CK. Interestingly, a nearly identical fraction of patients who were not tested for CK were instead referred to liver specialists, which may have been avoidable if CK had been checked. No patients with elevated CK progressed to severe muscle breakdown or required hospitalization. These findings suggest that automatically ordering CK when ALT/AST first become abnormal in statin users could help identify silent muscle problems and reduce unnecessary liver evaluations, while keeping patients on the right cholesterol treatment. • After new ALT/AST elevations in statin users, only 22.8% had CK tested within 30 days. • Among those tested, 15.8% had CK > ULN; 3.6% of the entire cohort had biochemical myopathy. • 4.7% of CK-untested patients were referred to GI within 60 days (roughly the same fraction as those with CK elevation) suggesting avoidable hepatic work-ups. • No cases of rhabdomyolysis, acute kidney injury, or hospitalization were documented. • A reflex CK at first abnormal transaminase may improve diagnosis and reduce unnecessary referrals. Transparency & Reproducibility Statement (recommended by PDS) • Protocol: Retrospective study design; not preregistered. Approved by the Cleveland Clinic IRB. • Data access: De-identified, aggregated data and a variable list are available from the corresponding author on reasonable request and with IRB/Institutional approval. • Code: Analysis code (SAS 9.4) will be shared on request. Reporting checklist: STROBE checklist completed and submitted. What is known about this subject • Small elevations in serum aminotransferases (ALT/AST) are commonly encountered in patients on statins, and aminotransferases can reflect both hepatic and muscle sources. • Current guideline recommendations do not require routine ongoing aminotransferase monitoring after statin initiation, and CK testing is not systematically performed after incidental transaminase elevations. • Failure to consider muscle as a source of aminotransferase elevations may lead to unnecessary hepatic evaluation and specialty referrals. What this study adds • In a real-world outpatient cohort of 806 statin users with new ALT/AST elevations, only 22.8% had CK measured within 30 days; among those tested 15.8% had elevated CK (3.6% of the overall cohort). • An identical ~3.6% fraction of the cohort who were not CK-tested were referred to gastroenterology, suggesting that absent CK data may be replaced by potentially avoidable hepatic work-ups. • Reflex CK measurement at the first abnormal transaminase in statin users could improve diagnostic accuracy and reduce low-value specialty referrals; prospective evaluation of such reflex-testing pathways is warranted. Patients on Statins With Elevated Transaminases: Frequency of Follow-up Creatine Kinase Testing and Gastroenterology Referral INTRODUCTION Hydroxymethylglutaryl‑CoA (HMG‑CoA) reductase inhibitors, more commonly known as statins, are widely prescribed for various conditions, most notably for the prevention and treatment of coronary artery disease (Thompson et al., 2016). Concerns regarding adverse effects, notably on liver enzymes and muscle toxicity, have prompted extensive research on how to monitor these effects best (Bader 2010; Thompson et al., 2016). Studies highlight risks such as myopathy, hepatotoxicity, and diabetes mellitus, with myopathy being dose‑dependent and hepatotoxicity manifesting as transient elevation in hepatic transaminases (Thompson et al., 2016; Bader, 2010). Currently, the FDA recommends initial liver enzyme tests be performed prior to statin initiation, but recommends against further monitoring as it does not appear to be effective (Wiklund et al., 2013). Whether or not monitoring is effective has long been debated (Lowe et al., 2013). This review synthesizes numerous studies that discuss the clinical implications of statin therapy and the need for nuanced risk assessment and monitoring strategies for optimal patient care. Findings from clinical trials may not provide a true picture of muscle complaints associated with statins, however (Fernandez et al., 2011). It has been shown that, in general, clinical trials tend to report lower rates of adverse symptoms than seen in clinical practice (Fernandez et al., 2011). The discrepancy between the experience of physicians in clinical practice and the findings of researchers in clinical trials may exist because clinical trials tend to include volunteers who have more positive drug expectations and higher tolerance of adverse effects than would be seen in primary care (Fernandez et al., 2011). Furthermore, the characteristic subject group in clinical trials is healthier and younger than those seen in clinical practice (Fernandez et al., 2011). The incidence of myopathy and rhabdomyolysis found in trials, therefore, might be an underestimation of rates found in clinical practice (Fernandez et al., 2011). Furthermore, although most muscle complaints are not dangerous and do not result in muscle damage or increased health risk, even benign muscle aches and pains can affect quality of life and motivate symptomatic patients to discontinue treatment (Thompson et al., 2016). To date, seven statin drugs have entered the market, beginning with lovastatin in 1987 (McKenney et al., 2006). Originally, the primary safety concerns were liver toxicity and the development of cataracts, with little concern for muscle abnormalities or pain (Rosenson 2004). Therefore, regular eye examinations and liver function tests were included in the initial drug trials for lovastatin, but creatine kinase (CK) measures were not (Rosenson 2004). Together, the rate for clinically relevant myopathy (muscle pain with CK elevations greater than 10 times the upper limit of normal [ULN]) in clinical trials for all statins (excluding cerivastatin) was 0.9 % of treated patients, but this was not significantly different than the placebo groups (Thompson et al., 2016). The average risk reduction for CVD and stroke with statin medication is 33.8 %, whereas the chance of fatal rhabdomyolysis is approximately one in 15 million prescriptions (McKenney et al., 2006). Statins lead to a rise in AST/ALT in certain people, which can be due to genetic predisposition, myopathy, necrotizing myopathy, rhabdomyolysis, and other reasons (Bader 2010). However, since AST and ALT are a panel of liver function tests (LFTs), the fact that they are coming from the muscles is many times not taken into consideration and patients with elevated ALT and AST do not end up getting their CK checked (Galarraga et al., 2003; Shaikh et al., 2021). With elevated AST/ALT, CK tends to be less frequently checked, leading to many missed diagnoses of statin‑induced clinically silent myopathies (Lowe et al., 2013). Aspartate aminotransferase (AST) was first described as a marker of myocardial injury by Karmen in 1955 (Karmen, 1955). Many organs, such as the heart, muscle, and liver, require aminotransferases to link protein and carbohydrate metabolism. Therefore, an elevation in AST/ALT cannot solely be taken as a marker of liver injury, and a CK should be checked to rule out muscle diseases (Shaikh et al., 2021). There is no current data on people who have undergone liver biopsies as a part of their workup for elevated AST/ALT, but never had their CK checked. METHODS The primary aim of this study was to determine how often creatine kinase (CK) levels were checked in patients receiving statins when alanine/aspartate aminotransferases (ALT/AST) became elevated. Because clinicians may attribute abnormal liver function tests to hepatic inflammation without assessing peripheral muscle disease, the secondary aim was to evaluate whether CK testing in patients with elevated liver function tests (LFTs) might avert unnecessary biopsies and gastroenterology (GI) referrals. We hypothesized that CK testing in this context would reduce unnecessary hepatic workups and better characterize the incidence of statin-associated myopathy in the outpatient setting. We conducted a retrospective chart review of outpatients within the Cleveland Clinic health system who were receiving statin therapy and had an elevated ALT or AST during the study period. We reviewed electronic health records to ascertain whether a CK level was obtained at the time of (or within 30 days of) the index transaminase elevation, and we recorded the specific statin used. The look-back period spanned up to 4–5 years, depending on the timing of Epic implementation at Akron General. Adults aged ≥18 years of any sex or race with a diagnosis of hyperlipidemia/dyslipidemia who were treated with a statin and had an elevated ALT or AST during the study period were included. Patients with elevated ALT/AST who were not receiving a statin were excluded. We restricted the cohort to patients seen in outpatient general medicine clinics. For patients meeting all inclusion criteria and no exclusion criteria, data were abstracted from written and electronic medical records (Epic). Abstracted data included demographics; diagnoses of hyperlipidemia/dyslipidemia; statin exposure (agent and, when available, dose); ALT/AST elevations (dates/values); whether and when CK was measured relative to the transaminase elevation; CK values; and comorbid liver disease. We also recorded GI referrals occurring within 60 days of the abnormal transaminase result. There was no control group. Categorical variables were summarized as frequencies and percentages and compared using Pearson χ² tests or Fisher exact tests, as appropriate. Normally distributed continuous variables were summarized as mean (SD) and compared with t tests; non-normally distributed continuous variables were summarized as median (interquartile range) and compared with Wilcoxon rank-sum tests. Logistic regression was used to assess associations between myopathy and statin use. A two-sided significance level of 0.05 was used for all tests. Analyses were performed using SAS® software, version 9.4 (SAS Institute Inc, Cary, North Carolina). A total of 806 adult outpatients on statin therapy met all inclusion criteria during the five-year query period (Figure 1). Baseline demographic characteristics are presented in Table 1. The population was predominantly White (77.4%), slightly female-predominant (53.6%), and largely older than 50 years (87.4%). Three charts (0.4%) lacked documentation indicating whether a creatine kinase (CK) level had been obtained; these were retained for baseline statistics but excluded from CK-specific analyses. Only 184 of 806 patients (22.8%) had a CK level drawn within one month of the first documented elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (Table 2). The median interval between transaminase elevation and CK measurement was nine days (interquartile range 5-17 days). The remaining 619 patients (76.8%) did not undergo CK testing in that time frame. Among 184 patients with timely CK tests, 29 (15.8%) exceeded the laboratory upper limit of normal (ULN)(Table 2). Nineteen patients (10.3%) had CK values of 401-1000 U/L, and five patients (2.7%) had values >1000 U/L; no chart documented rhabdomyolysis, acute kidney injury, or hospitalization related to the CK elevation. Of the 619 patients who did not have a CK ordered, 29 (4.7%) were referred to Gastroenterology within two months of the abnormal transaminase result for presumed hepatic evaluation (Table 2). None of the patients with an elevated CK level were referred to Gastroenterology. A concise comparison of clinically relevant proportions is provided in Table 3. Notably, the fraction of patients with biochemical evidence of muscle injury (3.6% of the entire cohort) mirrored the fraction of CK-untested patients who were referred for liver work-ups (also 3.6%), suggesting that lack of CK data may prompt potentially avoidable hepatology evaluations. Table 1: BASELINE PATIENT CHARACTERISTICS N=731 RACE, N (%) WHITE 77.4% AFRICAN- AMERICAN 14.7% ASIAN 2.3% MULTIRACIAL 4% AMERICAN INDIAN 0.2% SEX, N (%) FEMALE 53.6% MALE 46.3% AGE IN YEARS, N (%) 23-50 12.5% >50 87.4% Table 1. Baseline characteristics of the study subset with complete demographic data (N = 731). Values are n (%). Demographic variables were abstracted from the electronic health record at the time of the index transaminase elevation. Percentages may not sum to 100 because of rounding or missing data. Table 2: Variable n % of total (N = 806) % of row subgroup CK measured ≤ 1 mo after elevated AST/ALT 184 22.8 — —CK elevated (> ULN) 29 3.6 15.8 % of those tested —CK 401–1000 U/L 19 2.4 10.3 % of those tested —CK > 1000 U/L 5 0.6 2.7 % of those tested CK not measured ≤ 1 mo 619 76.8 — —GI consult ≤ 2 mo 29 3.6 4.7 % of untested pts CK status undocumented 3 0.4 — Table 2. Frequency, timing, and results of creatine kinase (CK) testing after an index ALT/AST elevation (N = 806). Shows the number and proportion of patients who had a CK measured within 1 month of the first documented alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation, the number and percent with CK above the laboratory upper limit of normal (ULN) and CK magnitude strata, and the number and percent of patients without timely CK testing who were referred to gastroenterology (GI) within 2 months. CK magnitude categories reflect the laboratory ULN strata used in analyses. Three charts (0.4%) lacked documentation of CK status and were excluded from CK-specific analyses. Abbreviations: CK = creatine kinase; ULN = upper limit of normal; GI = gastroenterology. Table 3: Metric Value Patients with any CK test within 1 month of transaminase elevation 22.8 % (184/806) Patients with elevated CK among those tested 15.8 % (29/184) Patients with elevated CK in the entire cohort 3.6 % (29/806) Patients without CK test who were referred to GI 4.7 % (29/619) Matching proportion (elevated CK vs GI referral of CK-untested) Both 3.6 % of total cohort Table 3. Key outcome proportions. Concise summary of principal outcome proportions used in the manuscript. Values shown: proportion with a CK test within 1 month of the index transaminase elevation, proportion with elevated CK among those tested, proportion with elevated CK in the entire cohort, proportion without CK testing who were referred to GI within 2 months, and the comparison of the matched proportions (elevated CK vs GI referral among CK-untested). Percentages are presented with raw counts in parentheses. Figure 1. Cohort selection flow diagram. Flow diagram showing the stepwise identification of the study cohort from the electronic health record query through application of inclusion and exclusion criteria, with the final analytic sample (N = 806). Numbers excluded at each step and the primary reasons for exclusion are indicated. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; EHR, electronic health record. DISCUSSION In this 5‑year cohort of 806 outpatient statin users with newly elevated aminotransferases, only 22.8 % underwent a creatine‑kinase (CK) test within 30 days, yet 15.8% of those tested (3.6% of the entire cohort) already showed CK levels above the laboratory upper limit of normal, signifying previously unrecognised muscle injury. Strikingly, an identical 3.6% of patients who never received a CK test were instead referred to Gastroenterology, indicating that missing CK data is often substituted by potentially avoidable hepatic work‑ups. None of the CK‑elevated patients progressed to rhabdomyolysis or required hospitalization, underscoring the subclinical nature of the myopathy being overlooked. For context, we applied conservative enzyme thresholds derived from pivotal statin‑safety trials (Heart Protection Study 2009; Dale et al., 2007): “significant” elevations were defined as > 3 × upper‑limit‑of‑normal (ULN) for ALT/AST (> 120 U/L) or > 5 × ULN for CK (> 1000 U/L), while “moderate” elevations encompassed 2–3 × ULN for ALT/AST (81–120 U/L) and 2.5–5 × ULN for CK (501–1000 U/L). A detailed review of the record of every patient with significant or moderate elevations of serum transaminase or CK values was performed to identify whether the abnormalities appeared to be directly attributable to statin use. An abnormal test result was considered attributable to statin use if it could be reasonably explained by no other medical condition or medication use, or if it resolved when the medication was discontinued. For example, if a patient had both an elevated CK serum level and a myocardial infarction, or both an elevated transaminase serum level and symptomatic cholecystitis, and if the abnormalities resolved over time despite continuation of the statin medication, the medication was not considered the cause of abnormal blood test results. Assuming an average cost of $32 and $23 for measurement of ALT and CK, respectively, the semiannual screening of all patients in our practice who take statin medications would cost more than $130,000 a year. This cost does not include the additional expense expected from further laboratory testing associated with minor abnormalities discovered during screening; more frequent monitoring, as practiced by many clinicians, would also increase the cost. If, however, only high-risk and symptomatic patients were evaluated, a significant reduction in overall cost and inappropriate drug discontinuation would likely follow, without compromising quality of care. However, a larger sample size would also help determine if one particular statin has a higher incidence of toxic effects, as has been suggested by recent reports linking cerivastatin with rhabdomyolysis. While prior studies have viewed transaminase values less than 3 times and CK values less than 10 times the upper limit of normal as not clinically relevant, a much longer follow-up would be needed to determine the long-term effect of these abnormalities. Finally, statins could be contributing to these abnormalities in patients with abnormal laboratory findings that persist and are attributed to other causes (such as hepatitis C or alcohol use). The safety of treating such patients with statin medications deserves further investigation. The relationship between statin therapy and liver function is a subject of ongoing investigation. Studies from Leaver et al and Onusko underscore the importance of monitoring liver enzymes, particularly alanine aminotransferase (ALT) and aspartate aminotransferase (AST), prior to statin initiation as well as maintenance (Leaver et al, 2009; Onusko, 2008). Leaver and colleagues further explained that monitoring lab values regularly in patients prescribed statins can reduce the potentially damaging effects (Leaver et al, 2009). In another study in 2016, Kim and colleagues evaluated the relationship between elevated liver function tests prior to statin therapy and whether the elevation increased risk in further elevation after beginning statin therapy (Kim et al, 2016). They found that the progression rate to abnormal AST/ALT values greater than 3x the upper normal limit was significantly higher in those with borderline AST/ALT compared to those with normal values (Kim et al, 2016). Due to these findings, they advised regular monitoring of AST/ALT levels in patients who have an initial elevation in AST/ALT prior to statin therapy initiation (Kim et al, 2016). In contrast to the above studies, Smith and colleagues conducted a study in 2003 aimed to determine the yield of routine screening of aminotransferases and CK levels among patients taking statins (Smith et al, 2003). Through a retrospective chart review, they discovered that routine lab monitoring revealed no cases of significantly or moderately abnormal transaminase values attributable to statins (Smith et al, 2003). Because of this, they further questioned obtaining routine lab monitoring in patients prescribed statins. In an additional study, Lowe and colleagues evaluated the frequency of outpatient liver function tests (LFTs), lipid panels, and CK for patients on chronic statin therapy to determine the efficacy of frequent lab monitoring (Lowe et al, 2013). They noted that any elevation in LFTs was less than three times the upper normal limit and that therapy was continued regardless of these laboratory changes with no adverse effects (Lowe et al). Similar to this, in 2011, Elhayany and colleagues studied the clinical impact of abnormal LFTs or muscle enzyme results with routine monitoring for those on statins. They found that of 408 patients who had one elevated enzyme level on routine monitoring, only 36 (8.8%) were symptomatic (Elhayany et al, 2011). 40 patients had further evaluation after the initial elevation, which resulted in only 2 symptomatic patients receiving treatment (Elhayany et al, 2011). Both studies emphasized that most of the regular laboratory monitoring in asymptomatic patients showed mild elevations in LFTs or creatinine kinase and resulted in no changes to their treatment regimen. They all reported little practical value in routine monitoring in the absence of symptoms (Lowe et al, 2013; Elhayany et al, 2011). Regarding high-risk patients, Armitage and colleagues conducted a randomized controlled trial in over 20,000 patients with either vascular disease or diabetes who were considered to be high risk (women, older individuals, low cholesterol levels) and prescribed simvastatin (Armitage et al, 2009). They found that over five years, there was a low incidence of myopathy (0.1%) and the risk of hepatitis was undetectable (Armitage et al, 2009). Because of these findings, they concluded that routine monitoring of liver function tests during treatment with simvastatin is not useful (Armitage et al, 2009). This raised the idea that considering individual risk factors and comorbidities is essential to mitigate adverse effects while maximizing therapeutic benefits. Further insight into statin-induced hepatotoxicity was evaluated in two 2011 studies that emphasized the safety of statins in patients with chronic liver disease (Zamor et al, 2011; Gillett et al, 2011). In 2011, Zamor and colleagues found that in western societies, many patients who had indications for statins also had concurrent liver disease, such as non-alcoholic fatty liver disease (NAFLD) (Zamor et al, 2011). They found that statins are well tolerated and proved to have a decline in aminotransferases compared with untreated patients and that the benefit that statins provided far outweighed the risk in patients with chronic liver disease (Zamor et al, 2011). Similarly, an expert consensus panel of hepatologists convened by the National Lipid Association concluded that chronic liver disease is not a contraindication to statin use (Gillette et al, 2011). Although routine monitoring is not recommended by the current literature, they did recommend checking transaminase levels before initiating therapy, 12 weeks after initiating therapy, or increasing the dosage and periodically thereafter due to preexisting liver disease (Gillette et al, 2011). Further considering risk factors, a study in 2010 determined that pravastatin was safer than atorvastatin in patients with advanced age, liver diseases like NAFLD, and systemic disorders (Liu et al, 2010). In 2016, Kim and colleagues conducted a small study that demonstrated that progression rates of AST/ALT were different amongst different statins (Kim et al, 2016). Specifically, pitavastatin is least likely to cause elevated AST/ALT, and fluvastatin is most likely to raise AST/ALT (Kim et al, 2016). However, this was a small study only conducted in Korean patients and warrants further investigation. In addition, Dale and colleagues conducted a study in 2007 that concluded that higher intensity hydrophilic statins are more likely to be associated with increases in transaminases, but high intensity lipophilic statins are more likely to be associated with increases in creatinine kinase (Dale et al, 2007). These studies raise the consideration that statin prescriptions could be tailored to patients’ comorbidities to decrease the rate of adverse effects. There have also been efforts to identify the effects of statin therapy in those with hyperlipidemia. In 2006, Kashani and colleagues concluded that statin monotherapy increases the risk for transaminase elevation but not myalgia, creatinine kinase, or rhabdomyolysis in those with preexisting hyperlipidemia (Kashani et al, 2006). In contrast to this, a study conducted in 2003 by Kiortis and colleagues studied the safety of statins and fibrates in those with obesity and hyperlipidemia compared to lean patients. They determined no statistically significant difference in safety after monitoring liver enzymes and determined that the administration of fibrates and statins to obese patients is equally safe as the use in lean patients (Kiortis et al, 2003). Concerns regarding statin-induced muscle toxicity, including myopathy and rhabdomyolysis, have also been extensively studied. In 2020, Abdallah and colleagues discuss a case of elevated liver enzymes in a patient with muscle weakness and fatigue that, amidst an extensive workup, showed no liver abnormalities (Abdallah et al, 2020). Despite removal of therapy, the patient’s liver enzymes and symptoms remained, but through further laboratory evaluation, they found a significantly elevated creatinine kinase with concern for myositis (Abdallah et al, 2020). They stressed the importance of recognizing that abnormalities in liver function tests are not solely reflective of just liver issues, and myopathy should be further investigated (Abdallah et al, 2020). Furthermore, a study from 2017 investigated biomarkers used to detect and diagnose rhabdomyolysis in those prescribed statins (Ruan et al, 2017). They found that aspartate transferase is associated with raised peak CK levels and severity of rhabdomyolysis (Ruan et al, 2017). This study further supports the association of liver enzyme elevation in the setting of myopathies such as rhabdomyolysis. The literature findings from various studies on statin therapy emphasize its efficacy in managing conditions like hyperlipidemia and preventing cardiovascular events, while also highlighting concerns about adverse effects such as myopathy and hepatotoxicity. Studies advocate for initial liver enzyme tests before statin initiation, but debate continues regarding the necessity of ongoing monitoring, particularly in asymptomatic patients. While some studies suggest routine monitoring is ineffective in detecting significant abnormalities, others emphasize the importance of tailored risk assessment and monitoring based on individual patient characteristics and comorbidities. Further research explores the effects of different statins on liver enzymes and the safety of statin therapy in high-risk populations, including those with chronic liver disease, finding statins to be helpful rather than harmful in this population. Concerns regarding muscle toxicity, including myopathy and rhabdomyolysis, have also been investigated, emphasizing the need for comprehensive evaluation beyond liver function tests to detect and manage adverse effects effectively. Overall, these studies contribute to a nuanced understanding of statin therapy’s benefits and risks, guiding clinicians in optimizing patient care strategies. CONCLUSION In this multi-center outpatient cohort, fewer than one in four statin-treated patients with newly elevated aminotransferases underwent timely creatine kinase testing, yet 15.8% of those tested—and 3.6 % of the entire cohort—demonstrated previously unrecognized CK elevations suggestive of subclinical statin-associated myopathy. An identical 3.6% of CK-untested patients were instead referred to Gastroenterology, implying that the absent muscle‐specific data can trigger potentially avoidable hepatic evaluations. Reflex CK measurement at the first detection of abnormal ALT or AST may therefore improve diagnostic accuracy, prevent unnecessary specialty referrals, and facilitate earlier, targeted adjustments to statin therapy while preserving its proven cardiovascular benefit. Prospective studies of reflex-testing algorithms—and statin selection and dose tailoring in high-risk subgroups—are warranted to confirm clinical and economic advantages. Ethics Statement This study was reviewed and approved by the Institutional Review Board of Cleveland Clinic, which granted a waiver of informed consent for this minimal risk retrospective chart review. Data Availability De-identified aggregate data underlying the results and the analysis code are available from the corresponding author upon reasonable request and with appropriate approvals. Conflicts of Interest The authors declare no conflicts of interest related to this work. Funding No external funding was received. Author Contributions Conceptualization: FS, RJ, AN; Methodology: FS, RJ, AN; Data curation: AK, RJ, AN; Formal analysis: FS, MM, IS; Investigation: AK, RJ, AN; Writing—FS, AK, RJ, AN: Writing—review & editing: [all authors]; Supervision: FS, MM, IS. REFERENCES 1. Thompson PD, Panza GA, Zaleski AL, Taylor BA. Statin-Associated Side Effects. J Am Coll Cardiol. 2016;67(20):2395-2410. doi:10.1016/j.jacc.2016.02.071 2. Bader T. The Myth of Statin-Induced Hepatotoxicity. Am J Gastroenterol. 2010;105(5):978-980. doi:10.1038/ajg.2010.102 3. Wiklund O, Pirazzi C, Romeo S. Monitoring of Lipids, Enzymes, and Creatine Kinase in Patients on Lipid-Lowering Drug Therapy. 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Collection British Journal of Clinical Pharmacology Authors Affiliations Faris Shweikeh [email protected] Cleveland Clinic Akron General Department of Internal Medicine View all articles by this author Anas Kartoumah 0009-0006-7269-498X University of South Florida Tampa Bookstore View all articles by this author Rajshri Joshi Cleveland Clinic Akron General Department of Internal Medicine View all articles by this author Anjali Nadihaan Cleveland Clinic Akron General Department of Internal Medicine View all articles by this author Mohammed Mouchli University of South Florida Tampa Bookstore View all articles by this author Inderprit Singh Fisher-Titus Medical Center View all articles by this author Metrics & Citations Metrics Article Usage 458 views 97 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Faris Shweikeh, Anas Kartoumah, Rajshri Joshi, et al. 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